Background. The cause of polycythemia vera, which originates from a multipotent hematopoietic progenitor cell, is unknown. Thrombopoietin is a hematopoietic growth factor that regulates the production of multipotent hematopoietic progenitor cells and platelets. To evaluate the possibility that an abnormality in thrombopoietin-mediated signal transduction might be involved in the pathogenesis of polycythemia vera, we examined thrombopoietin-induced tyrosine phosphorylation of proteins and the expression of the thrombopoietin receptor in platelets from patients with the disease. Methods. Platelets were isolated from the blood of patients with polycythemia vera or other chronic myeloproliferative disorders and control subjects. The platelets were exposed to either thrombopoietin or thrombin and then lysed for analysis of tyrosine phosphorylation of platelet proteins and the expression of the proteins by means of immunoblotting. Expression of the thrombopoietin receptor (Mpl) by platelets and megakaryocytes was also assessed. Results. Thrombopoietin-mediated tyrosine phosphorylation of proteins was impaired in platelets from 20 patients with polycythemia vera and 3 with idiopathic myelofibrosis, but not in 4 patients with essential thrombocytosis, 3 with chronic myelogenous leukemia, 6 with secondary erythrocytosis, 2 with iron-deficiency anemia, 4 with hemochromatosis, or 5 normal subjects. Thrombin-mediated tyrosine phosphorylation of proteins was intact in platelets from patients with polycythemia vera, and the tyrosine kinases and substrates involved in the process were present in normal amounts. However, expression of the platelet thrombopoietin receptor Mpl was markedly reduced or absent in 34 of 34 patients with polycythemia vera and in 13 of 14 patients with idiopathic myelofibrosis. Impaired thrombopoietin- induced tyrosine phosphorylation of proteins in patients with these two diseases was uniformly associated with markedly reduced expression of Mpl or the lack of its expression. In patients with polycythemia vera, reduced expression of Mpl by platelets was associated with reduced expression of Mpl by megakaryocytes. Conclusions. Reduced expression of the thrombopoietin receptor Mpl is characteristic of polycythemia vera and idiopathic myelofibrosis. The abnormality appears to distinguish polycythemia vera from other forms of erythrocytosis.
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